Suicide is a major public health concern, and the 11th leading cause of death in the United States. The rate of suicide in the US is 11 per 100,000. In 2003, there were over 30,000 deaths by suicide. During the present funding period, we found changes in serotonin neurons that appear to be functionally in the opposite direction to changes in the cortical terminal fields. We propose a new biologic model of suicide where the terminal field changes are indicative of impaired serotonin transmission, while the serotonin neurons indicate a compensatory or homeostatic response. We propose to further test this model by doing more detailed dorsal raphe subnuclei analyses since our receptor mapping studies suggest that the serotonin terminal field effects associated with suicide are not widespread but are confined to certain parts of the ventral prefrontal cortex and other brain regions, suggesting that not all parts of the DRN and MRN are involved. We also seek to prove a specific relationship to suicide by studying suicide in two different major psychiatric disorders. We will examine fully characterized groups of depressed suicides (MOD, n=15), schizophrenic suicides without major depression (SZ, n=15) and non-psychiatric controls (n=15). In this revised application, we have addressed the concerns of the reviewers and propose the following specific aims. Specific Aim 1. We will determine whether the expression levels of neuronal tryptophan hydroxylase (TPH2) mRNA in neurons of the dorsal (DRN) and median (MRN) raphe nuclei in suicides are altered at the level of individual neurons in suicides relative to nonpsychiatric controls. We will also determine whether transcript levels are altered throughout the DRN and MRN or localized to specific DRN subnuclei. We hypothesize that MOD and SZ suicides will overexpress TPH2 at a per neuron level in the DRN and MRN, and that this effect will be confined to certain subnuclei. Specific Aim 2. We will quantify TPH2-IR in serotonin nerve terminals in the prefrontal cortex (PFC, ventral and dorsal). Given the data indicating supporting impaired serotonin transmission in the cortex, we hypothesize that the TPH2-IR will be lower in the ventral prefrontal cortex of suicides contributing to deficient levels of serotonin. Changes in dorsal PFC will be related to MOD or SZ. Specific Aim 3. We will determine whether the non-serotonergic DRN and MRN neurons are GABAergic. Our pilot data suggest fewer non-serotonergic neurons in the DRN and we hypothesize that there will be fewer GABA neurons in the DRN of suicides. Our study will help differentiate the neurochemical correlates of MOD or SZ versus suicide at the level of source (DRN and MRN) neurons and target cortical elements. [unreadable] [unreadable] [unreadable]